POSTNATAL MATURATION OF SEROTONIN SIGNALING SYSTEM IN MOUSE DUODENUM

Abstract

BACKGROUND AND AIMS: A plethora of study in animal neurodevelopmental models demonstrate that in central nervous system (CNS) temporal differences occur in the maturation of different neurotransmitter systems (Goldman-Rakic & Brown, 1982, Ehrlich et al., 2013). Although significant advances have been made in understanding the modifications in CNS, only primarily descriptive studies about the changes taking place in enteric nervous system (ENS), main regulator of gastrointestinal (GI) functions, have been underway. As the other organ systems, digestive system is still developing and maturing after birth and thus it is possible to speculate that the changes in the chemical coding of ENS may occur with development. Studies about the postnatal maturation of enteric neurotransmitter systems could help to assess why drugs, able to modulate GI functions, may have diverse clinical effects at different ages. Serotonin (5-hydroxytryptamine or 5-HT), is an important enteric neurotransmitter in the GI tract (Gershon 2013). Neuronally-released 5-HT plays a crucial role in the regulation of several physiological functions, such as motility, secretion and visceral sensitivity (Gershon 2013; Baker 2005; Beattie & Smith 2008). Since serotoninergic system appears to undergo dramatic postnatal changes in CNS, in this study we aimed to assess if, in the enteric nervous system, 5-HT signalling may undergoes to postnatal maturation, using mouse duodenum as model. METHODS: Using a pharmacological approach, we examined, in vitro , the role of 5-HT signalling in the regulation of duodenal contractility in neonatal mice (2 days old) compared to the adults. RESULTS: 5-HT induced in both duodenal preparations a concentration-dependent muscular contraction, being its efficacy greater in duodenum from neonatal mice. Serotoninergic response was mediated by activation of muscular 5-HT receptors, antagonized by methysergide, nontarget 5-HT receptor antagonist, and of neural 5-HT 3 receptors, antagonized by ondasetron. In both preparations there was a major sensitivity of the postjunctional vs prejunctional receptors. In duodenum from neonatal mice pretreatment with atropine, muscarinic receptor antagonist, abolished neurally evoked serotoninergic contraction. Instead, in adult duodenum, in the presence of atropine, the response to 5-HT was converted in a muscular relaxation, abolished by L-NAME, a nitric oxide (NO) synthase inhibitor. L-NAME per se potentiated the 5-HT cholinergic contractile effects in adult preparations. Instead, L-NAME was ineffective in neonatal preparations. CONCLUSIONS: In mouse duodenum, 5-HT signaling undergoes to age-related changes. In both preparations, 5-HT induces contractile effects via activation of muscular receptors and neural 5-HT 3 receptors on cholinergic nerves to induce acetylcholine release. Contractile response to 5HT is detectable from birth, but there is a gradual decrease in efficacy with age and a concurrent recruitment of inhibitory nitrergic nerves. These changes may contribute to gut motility adaptation to cope with the dietary changes at weaning. REFERENCES Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch Pharmacol. (2008) ;377:181-203. Ehrlich DE, Ryan SJ, Hazra R, Guo JD, Rainnie DG. Postnatal maturation of GABAergic transmission in the rat basolateral amygdale J Neurophysiol.; (2013) 110:926-41. Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. (2013) 20:14-21. Goldman-Rakic P, Brown R Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Dev Brain Res (1982) 4:339 – 349